HIV/AIDS continues to be a major global public health issue with the threat of emerging, multi-drug resistant viral strains, and therefore it is also a very considerable economic issue. At the end of 2014 approximately 1 million people were living with HIV/AIDS in the US and 36.9 million people worldwide; 2 million became newly infected with AIDS in 2014. The epidemic continues to devastate even the US with some 50,000 new HIV infections each year. Despite modern combination therapies, HIV remains a considerable challenge and threat because of a rapid rise in multi-drug resistant strains. Resistance to one or more of the drugs in combination was inevitable. Millions of patients have strains of HIV that resist one or more of the currently available HIV therapies. To overcome HIV?s drug resistances, new validated targets and novel therapeutics are urgently needed. Sirga Advanced Biopharma (Sirga) is meeting this challenge with the discovery of small molecule drugs that interrupt an interaction between human cells and the virus - an interaction that is absolutely essential for viral replication and propagation. This particularly critical interaction is also one that Sirga scientists have investigated as being refractory to the emergence of drug resistance. Though interactions of host cell and viral proteins are the considered important targets of interaction, the interaction of the host RNA with viral proteins has not as yet been exploited as sites of intervention for new therapeutics, except by Sirga. Sirga?s initial research program has been extremely successful in identifying three families of the small molecules that specifically inhibit HIV replication including drug resistant strains, has low cell cytotoxicity and in very preliminary mouse testing indicated no-toxicity at mgs/kg body weight. In this Phase I research proposal, Sirga will develop these Hit compounds with its own derivative chemistries into promising Lead compounds for novel drug discovery. Sirga will determine the mechanism of action of the pharmacologically and structurally diverse putative drugs, and explore and optimize bioactive small molecule derivatives (Structure/Activity Relationships) with little to no cell and animal toxicity. The most promising of compounds will be assessed as antiviral agents against drug resistant strains of HIV. The goal is to develop two or three promising Hit molecules into Lead molecules for treating HIV/AIDS by disrupting a novel RNA/protein function found only in infected cells. The outcome of these Aims will be measureable. The mechanism of action of the compounds as novel inhibitors of viral assembly will be confirmed. Sirga will identify of 2 or 3 tractable Leads with convincing SAR, high in vitro potency (? 1 M), and effective non-toxic concentrations in the nM range in cells and the range of mg/kg weight in animals. These criteria will be almost comparable to current FDA-approved anti-HIV drugs and will position the Company to propose Phase II research.